Disruptive agitation emerges as a distressing and often persistent group of behaviors during the disease course of the majority of persons with Alzheimer's disease (AD). It greatly increases caregiver burden in both the home and long-term care settings, is a leading precipitant of nursing home placement, and causes suffering in patients and stress and increased burden in the caregiving environment. Disruptive agitation is likely the most important reason for the widespread prescription of psychotropic medications in AD and related dementias. Among the psychotropics, only the antipsychotics have been consistently demonstrated superior to placebo for these distressing symptoms. However, effect sizes are modest, nonresponders frequent, adverse effects common, and an increased risk for death and cerebrovascular adverse events in multiple large clinical trials of atypical antipsychotics prompted a "black box warning" from the FDA re: their use in persons with dementia. It is clear that finding new pharmacologic approaches to reducing disruptive agitation in AD is an important clinical goal. This application proposes a placebo-controlled pilot trial of the generically available brain active alpha-1 adrenoreceptor (AR) antagonist, prazosin, for disruptive agitation in AD. Clinical studies in AD patients and AD brain tissue suggest that enhanced responsiveness to norepinephrine (NE) at central nervous system (CNS) alpha-1 ARs contributes to disruptive agitation in AD. Strongly positive preliminary data from an open label trial and a small placebo-controlled feasibility trial of prazosin in AD patients with severe disruptive agitation support potential efficacy and good tolerability in this frail elderly population. We will randomize 128 AD patients with persistent disruptive agitation to prazosin (maximum dose 4 mg b.i.d.) or placebo in a 12-week double-blind trial. Maintenance medications will be kept constant during the trial. Primary outcome measures are the Alzheimer's Disease Cooperative Study (ADCS) Clinical Global Impression of Change and the Neuropsychiatric Inventory total score. Secondary outcome measures are the Brief Psychiatric Rating Scale (BPRS) total score, BPRS Agitation Factor, ADCS-Activities of Daily Living-19, and the Mini Mental State Exam. The following hypotheses will be tested: 1a) AD patients randomized to prazosin will have a greater reduction in disruptive agitated behaviors than those randomized to placebo;1b) total dose of "rescue" lorazepam will be lower in prazosin than placebo subjects;1c) time to study discontinuation ("dropout") due to continued agitation will be greater in prazosin than placebo groups;and 1d) time to study discontinuation ("dropout") due to adverse effects will not differ between prazosin and placebo groups. At the completion of the 12-week placebo-controlled phase, all subjects will receive an additional 12 weeks of open label prazosin to gather observational data on the resiliency of the predicted therapeutic effect of prazosin for disruptive agitation. If results of this pilot study are positive, we will pursue a large definitive multisite study through the Alzheimer's Disease Cooperative Study mechanism. PUBLIC HEALTH RELEVANCE: Disruptive agitation in Alzheimer's disease (AD) occurs in the majority of patients over the course of their illness. This syndrome is a major source of patient and caregiver distress and nursing home placement, and current treatment approaches often are inadequate. This application proposes a placebo-controlled trial of the generic drug prazosin for disruptive agitation in AD. Prazosin blocks the excessive brain adrenaline arousal that contributes to agitation in AD and both therapeutic and tolerability results of our prazosin feasibility study are very promising.